Cyclosporin formulation

ABSTRACT

Provided are therapeutic compositions which provide high bioavailability of the active ingredients from the group of cyclosporin, at the same time permitting concentrations in dosage forms higher than 10%.

This application is a 371 of PCT/GB97/02079 filed Jul. 31, 1997.

This application is made under the provision of 35 U.C.S. §371.

BACKGROUND OF THE INVENTION

The invention relates to pharmaceutical formulations including, as theactive ingredient, a therapeutically active cyclosporin.

Cyclosporins are a group of monocyclic, poly-N-methylatedundecapeptides, which are naturally produced as secondary metabolites bycertain fibrous fungi, especially of genera Tolypocladium andCylindroqarpon. Some therapeutically useful cyclosporins can be preparedby partial synthesis or by special fermentation procedures.

Ciclosporin (Cyclosporin A) is the first natural substance havingselective immunosuppressive effect on lymphoid cells, especially Tlymphocytes. It also influences functions of other cells of the immunesystem to a great extent.

Therapy makes use especially of effects of systemically administeredcyclosporins in organ transplantations or transplantations ofbone-marrow. They can be employed as well for treating a wide variety ofautoimmune diseases with inflammatory etiology and as anti-parasiticagents.

Certain cyclosporins without immunosuppressive activity exhibit aninhibitor effect towards replication of the HIV-1 virus and can beemployed in therapy for treatment and prevention of AIDS or AIDS relatedcomplex. The group of cyclosporins includes also chemomodulators usefulfor influencing cross resistance of tumor cells to cytostatics.

Bioavailability of cyclosporins in the organism is influenced, on onehand, by specific properties of this group of substances, but also bythe composition and properties of the particular dosage form. Animportant role in formulating therapeutic compositions containingcyclosporins is played by their high lipophilicity.

Solubility of these active substances in water typically does not exceed2.5 mg/100 ml, which value is approximately 100 times lower than neededfor regular absorption in the organism. The marked lipophilicity ofcyclosporins is evidenced by the values of their partition coefficientsP in the system n-octanol/water. For ciclosporin, values of log P=21.08to 2.99 have been reported.

To achieve acceptable bioavailability of cyclosporins, especially thoseformulations are used in practice and are patented which form, whenneeded, dispersion systems characterised by the presence of ahydrophilic phase, a hydrophobic phase and a tensoactive component. Theresulting dispersions are either classic emulsions or opticallytransparent microemulsions. Commercially available compositions for oraladministration, known under the trade names Sandimunn®,Sandimunn®-Neoral, Consupren®, Implanta®, Imusporin® as described in GB2015339, GB 2222770, GB 2270842, GB 2278780 and equivalents are based onthis general principle.

Modifications of the preceding systems, where the hydrophilic base isomitted and replaced by partial esters of fatty acids with polyols likepropylene glycol, glycerol or sorbitol, are described in GB 2228198.

German patent application DE 4322826 discloses, as the carrier systemfor drugs poorly soluble in water, a composition containing polyglycerylesters of fatty acids as a co-tenside to non-ionic tensides having HLBhigher than 10, in the presence of a triacyl glycerol as the lipophiliccomponent.

Formulations containing cyclosporins in a vehicle comprising propyleneglycol, mixed mono-, di- and triglyceride and a hydrophilic tenside,disclosed in GB patent 2248615, are typical microemulsionpreconcentrates of the oil-in-water type.

A reverse "water-in-oil" type of the microemulsion preconcentratecontaining cyclosporins defined as L₂ phase is disclosed in SE 95024725.

Commercially available oral cyclosporin compositions are provided assolutions or in soft gelatin capsules. Disadvantages of solutionformulations provided as self-emulsifying concentrates for dilution whenneeded are poor patient acceptability and toxicity concerns.

Soft gelatin capsules mask the taste of the contents, but theirpreparation is expensive and requires special packing to avoid migrationof ethanol through the wall of the capsule into the packing environment.

Some solvents for example propylene glycol, low-molecular polyethyleneglycols, diethyleneglycol monoethyl ether, tetrahydrofurfuryl alcoholether, which may be present in the contents or fill of the soft gelatincapsules, are liable to migrate into the capsule shell. Such capsulesare not stable, because the shells tend to soften due to migratingsolvents. Consequently the capsules may be deformed due to reduction ofthe volume of the contents and decrease of the pressure inside thecapsule. An approach to solve these problems disclosed in GB-A-2282586consists in adding solvents able to migrate into the capsule shellfollowed by reduction of the resulting tackiness of the gelatin bycooling during production.

This invention is directed to therapeutic compositions which providehigh bioavailability of the active ingredients from the group ofcyclosporin, at the same time permitting concentrations in dosage formshigher than the usual 10%.

The aim of this invention is to omit polar solvents in the therapeuticcompositions in order to avoid the previously described undesirableeffects.

According to the present invention a pharmaceutical composition forinternal use, contains, as the active ingredient, 10 to 25% by weight ofa cyclosporin, and a carrier composed of (i) one or more partial estersof C₆ to C₂₂ fatty acids with a glycerol derivative selected from:diglycerol to decaglycerol and (ii) partial esters of C₈ to C₁₆ fattyacids with pentaglycerol to pentadecaglycerol in mutual weight ratios(i):(ii) of 1:1 to 1:5, optionally containing additional adjuvants.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 2 and 3 illustrate histograms of particle frequencies and sizesresulting form the experiments described in Example 2.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

It should be understood for the purposes of this description that a"carrier" means a pharmaceutic adjuvant in which the active substance isdissolved or dispersed in an absorbable form. When required the carriercan also contain further excipients such as antioxidants, tastecorrecting agents and the like.

The formulations according to this invention can be liquid at theambient temperature or can be prepared as solids with the use ofcarriers having a melting point above ambient temperature. Theingredients of the carrier can be mixed together with the activesubstance at temperatures above the melting point before cooling to atemperature suitable for grinding to powdery granules for furthertreatment, eg for filling into bipartite capsules or sachets fordispersing as required. The liquid formulations, due to their viscouscharacter, may be employed especially for filling into bipartitecapsules. The capsules can then be treated, eg with an acid-resistantcoating, for use in treatment of auto-immune diseases of the intestinaltract.

The partial esters of polygylcerol with fatty acids used as componentsof the carrier may have the general formula

    HO--CH.sub.2 --CHOH--CH.sub.2 (O--CH.sub.2 --CHOH--CH.sub.2).sub.x --O--CH.sub.2 --CHOH--CH.sub.2 --OH

wherein x=0 to 13. Preferred partial esters are characterised by thefollowing data:

    ______________________________________                                                          Number of OH hydroxyl                                                mol.weight                                                                             groups       value                                          ______________________________________                                        diglycerol 166        4            1352                                       triglycerol                                                                              240        5            1169                                       tetraglycerol                                                                            314        6            1071                                       pentaglycerol                                                                            388        7            1012                                       hexaglycerol                                                                             462        8            970                                        heptaglycerol                                                                            536        9            941                                        octaglycerol                                                                             610        10           920                                        nonaglycerol                                                                             684        11           903                                        decaglycerol                                                                             758        12           880                                        pentadecaglycerol                                                                        1228       17           846                                        ______________________________________                                    

Fatty acids suitable for esterification of polyglycerol include, purenon-branched saturated and unsaturated fatty acids as well as mixturesof fatty acids obtained by hydrolysis from natural fats and oils. Theacids may also be substituted, for example 1,2-hydroxyoleic acid, orbranched, for example isostearic acid.

Partial esters of polyglycerols with the C₈ to C₂₂ fatty acids aregenerally prepared either by esterification of polyglycerols withcorresponding saturated or unsaturated acids or by trans-esterificationof vegetable oils with polyglycerols. Each individual partial ester ofpolyglycerols may be characterised by its saponification number.

The degree of polymerisation may be indicated by the hydroxyl value.Products which are especially suitable as component (i) of the carrierinclude:

    ______________________________________                                        diglyceryl monooleate                                                                            NIKKO ® DGMO-90                                        triglyceryl monooleate                                                                           DANISCO TS-T 122                                           tetraglyceryl monostearate                                                                       NIKKO ® Tetraglyn 1-S                                  tetraglyceryl monooleate                                                                         NIKKO ® Tetraglyn 1-0                                  decaglyceryl trioleate                                                                           NIKKO ® Decaglyn 3-0                                   decaglyceryl tristearate                                                                         NIKKO ® Decaglyn 3-S                                   decaglyceryl pentaoleate                                                                         NIKKO ® Decaglyn 5-0                                   ______________________________________                                    

Preferred compounds which may be used a s component (ii) of the carrierinclude:

    ______________________________________                                        hexaglyceryl monolaurate                                                                         NIKKO ® Hexaglyn 1-L                                   hexaglyceryl monococoate                                                                         --                                                         hexaglyceryl monomyristate                                                                       NIKKO ® Hexaglyn 1-M                                   decaglyceryl monolaurate                                                                         NIKKO ® Decaglyn 1-L                                   decaglyceryl monomyristate                                                                       NIKKO ® Decaglyn 1-M                                   ______________________________________                                    

Preferred components (i) of the carrier are lipophilic fat-likesubstances (pseudo-lipids). They have very low toxicity. The acceptabledaily dose (ADI) for the polyglycerols was determined by FAO/WHO in 1975as 25 mg/kg body weight. That is ten times greater than the acceptabledose for fatty acid microesters, which are suggested as a carrier forcyclosporin formulations in GB patent 2230440. Components (i) of thecarrier include partial esters of long chain fatty acids. They dissolvethe active substances well and are needed for absorption of cyclosporinsfrom the gastrointestinal tract by the mechanism of formation of mixedmicelles, in which bile acids are involved.

Preferred components (ii) include medium to long chain fatty acids. Theymay have an amphiphilic character, but retain their ability to dissolvecyclosporins. These acids may effect the surface tension of the mixedcarrier and facilitate dispersion of the resulting combination in water.Even with a great excess of water these acids may form a physicallystable dispersion having an average particle size below 2 μm. This is apreferred condition for uniform absorption of the active substance. Theproducts of hydrolysis of partial esters of medium long fatty acids withglycerols are absorbed by another mechanism even in the absence of bileacids. That is especially advantageous in some diseases with reducedrelease of bile.

The whole group of the especially preferred partial esters of fattyacids with polyglycerols, useful as the carriers of the activesubstance, is characterised by one or more of the following criteria:

    ______________________________________                                        acid number        max. 6                                                     fatty acid Na salts content                                                                      max. 2% (as Na stearate)                                   heavy metal content                                                                              max. 10 ppm                                                water content      max. 2%                                                    total ash          max 1%                                                     iodine number      50-110 (unsaturated acid                                                      esters)                                                                       max. 3 (saturated acid                                                        esters)                                                    saponification number                                                                            100-180                                                    ______________________________________                                    

Polyglyceryl esters of fatty acids are physiologically more acceptable.adjuvants in comparison with polyoxyethylated tensides, which arecommonly used in commercially available ciclosporin compositions. Theydo not contain any residues of ethylene oxide monomer or its conversionproducts such as 1,4-dioxane.

The invention is further described by means of example but not in anylimitative sense with reference to the accompanying drawings of whichFIGS. 1, 2 and 3 depict histograms of particle frequencies and sizes ina composition of Example 2. The horizontal axis shows particle size inpm and the vertical axes show frequencies of the correspondingparticles.

EXAMPLE 1

Hard Gelatin Capsules

A formulation was prepared using the following ingredients:

    ______________________________________                                        ciclosporin        16.00 kg                                                   diglyceryl dioleate                                                                              24.00 kg                                                   decaglyceryl monomyristate                                                                       60.00 kg                                                   ______________________________________                                    

In a Frymix processing device, the diglyceryl dioleate was mixed withdecaglyceryl myristate at 60° C. Ciclosporin was added and mixing in anevacuated vessel was continued until dissolution occurred. The warmproduct was filtered and filled into hard gelatin capsules in amountscorresponding to 100 mg, 50 mg and 25 mg of the active ingredient,resp., on a Zanussi AZ-40 machine.

EXAMPLE 2

Hard Gelatin Capsules

A formulation was prepared using the following ingredients:

    ______________________________________                                        ciclosporin        14.30 g                                                    diglyceryl monooleate                                                                            33.36 g                                                    decaglyceryl monolaurate                                                                         52.37 g                                                    ______________________________________                                    

In a jacketed glass vessel, the diglyceryl monooleate was mixed withdecaglyceryl monolaurate by sonicating with an ultrasonic probe whilecooling to 70° C.

Ciclosporin was dissolved in the mixture during 3 minutes and the warmsolution was filtered through a filter having absolute particleseparability of 5 μm. The composition was filled into hard gelatincapsules in amounts corresponding to 100 mg, 50 mg an 25 mg of theactive ingredient, respectively.

The physical stability of the emulsion formed by dispersing the fillingof the capsule in water in a weight ratio of 1:50 was demonstrated by acomparison of the particle size as a function of time and the place ofevaluation.

    ______________________________________                                                       average  minimal                                                                              maximal                                        time place of  size     size   size                                           [h]  evaluation                                                                              [μg]  [μg]                                                                              [μm] histogram                              ______________________________________                                        0    middle    1.68     0.18   6.38    FIG. 1                                 4    surface   1.51     0.18   4.53    FIG. 2                                 4    bottom    1.66     0.18   5.13    FIG. 3                                 ______________________________________                                    

The histograms of the frequencies and sizes of the particles are shownin FIGS. 1, 2 and 3.

EXAMPLE 3

Starch Capsules

A formulation was prepared from the following ingredients:

    ______________________________________                                        ciclosporin        18.00 g                                                    tetraglyceryl monostearate                                                                       14.50 g                                                    decaglyceryl monomyristate                                                                       67.50 g                                                    ______________________________________                                    

Ciclosporin was dissolved in a melt of tetraglyceryl monostearate anddecaglyceryl monomyristate at 70° C.

The solid solution was charged into an extruder at the ambienttemperature and pellets were prepared from the extrudate by spheronizingand was filled into bipartite starch capsules.

EXAMPLE 4

Soft Gelatin Capsules

A formulation was prepared from the following ingredients:

    ______________________________________                                        ciclosporin        10.00 kg                                                   diglyceryl monooleate                                                                            35.00 kg                                                   decaglyceryl monolaurate                                                                         55.00 kg                                                   ______________________________________                                    

The diglyceryl monooleate was mixed in a Frymix processing device withdecaglyceryl monolaurate at 60° C. Ciclosporin was added and mixing inan evacuated vessel was continued until the ciclosporin dissolved. Thewarm product was filtered and filled into soft gelatin capsules inamounts corresponding to 25, 50 and 100 mg of ciclosporin.

EXAMPLE 5

Granulate in Sachets

A formulation was prepared from the following ingredients:

    ______________________________________                                        ciclosporin        18.00 kg                                                   tetraglyceryl tristearate                                                                        14.00 kg                                                   decaglyceryl monomyristate                                                                       68.00 kg                                                   xylitol            20.00 kg                                                   ______________________________________                                    

The tetraglyceryl tristearate was mixed in a Frymix with decaglycerylmonomyristate at 70° C. and the ciclosporin was dissolved therein. Tothis solution was added the crystalline form of xylitol having themelting temperature of 61° C. and the mixture was thoroughly mixed. Thecooled mixture was granulated and filled into sachets 2 g each (=300 mgof ciclosporin). The contents of the sachet were stirred into 50 ml ofwater before drinking.

What is claimed is:
 1. A pharmaceutical composition for internal use,comprising:10% to 25% by weight of a cyclosporin; and a carriercomprising,(i) one or more partial esters of C₁₆ to C₂₂ fatty acids witha glycerol derivative selected from the group consisting of diglycerolto decaglycerol and, (ii) one or more partial esters of C₈ to C₁₆ fattyacids with a glvcerol derivative selected from the group consisting ofpentaglycerol to pentadecaglycerol in mutual weight ratios (i):(ii) of1:1 to 1:5.
 2. A composition as claimed in claim 1, wherein the activecyclosporin is selected from the group consisting of [NVa]²-ciclosporin, [Melle]⁴ -ciclosporin and [3'-0-acylMeBml]¹ -ciclospor. 3.A composition as claimed in claim 1, wherein the glycerol derivativesare selected from the group consisting of diglycerol, triglycerol,tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octaglycerol,nonaglycerol, decaglycerol, and pentadecaglycerol.
 4. A composition asclaimed in claim 1, wherein the component (i) is selected from the groupconsisting of diglyceryl monooleate, triglyceryl monooleate,tetraglyceryl monostearate, tetraglyceryl monooleate, decaglyceryltrioleate, decaglyceryl tristearate, and decaglyceryl pentaoleate.
 5. Acomposition as claimed in claim 1, wherein the component (ii) isselected from the group consisting of hexaglyceryl monolaurate,hexaglyceryl monococoate, hexaglyceryl monomyristate, decaglycerylmonolaurate, and decaglyceryl monomyristate.
 6. A composition as claimedin claim 1, wherein component (i) is selected from the group consistingof diglyceryl monooleate, diglyceryl dioleate and triglyceryl monooleateand compound (ii) is selected from the group consisting of hexaglycerylto decaglyceryl monolaurate.
 7. A composition as claimed in claim 1,comprising a shape-specific or shape-non-specific dosage form with anominal content of 10 mg to 300 mg of the active ingredient per dose. 8.A composition as claimed in claim 1, wherein the dosage form is a liquidor easy melting filling of the active ingredient in the carrier,disposed in bipartite gelatin or starch capsules.
 9. A composition asclaimed in claim 1, further comprising additional adjuvants.